Intraocular irrigating solution having improved flow characteristics

ABSTRACT

Improved intraocular irrigating solutions are described. The solutions have enhanced viscosities that reduce the risk of damage to intraocular surgical procedures by reducing the turbulence of the solutions and dampening the movement of tissue fragments and air bubbles. The solutions preferably also have modified surface tensions that more closely resemble the surface tension of the aqueous humor.

The present application is a 371 of international Patent ApplicationNumber PCT/US01/48094 filed Dec. 11, 2001, which claims benefit of U.S.Provisional Application Ser. No. 60/257,570, filed Dec. 20, 2000.

BACKGROUND OF THE INVENTION

The present invention is directed to the field of intraocular surgery.More specifically, the invention is directed to the irrigation ofintraocular tissues during cataract surgery, vitrectomy surgery, andother intraocular surgical procedures. The invention providesintraocular irrigating solutions that have improved physical properties(e.g., flow characteristics) relative to prior ophthalmic irrigatingsolutions.

The field of intraocular surgery has advanced dramatically over the pasttwenty years. The advancements in this art have resulted fromsignificant improvements in the areas of surgical techniques, surgicalequipment and associated pharmaceutical products. Despite theseadvancements, intraocular surgery is still a very delicate process withlittle room for error and great potential for harm to both oculartissues and, ultimately, the vision of the patient. Thus, there is anongoing need to improve ophthalmic surgical techniques and equipment, aswell as associated pharmaceutical products.

The present invention has resulted from an effort to improve the fluiddynamics of intraocular irrigating solutions, so as to provide greaterprotection for delicate intraocular tissues, while at the same timeenhancing the ability of ophthalmic surgeons to perform surgicalprocedures more efficiently.

Although various techniques have been used previously to remove thenatural crystalline lens of the eye when it becomes afflicted with acataract, the majority of cataract surgeries today are performed byusing a procedure known as “phacoemulsification”. This procedureinvolves the use of a surgical handpiece having a tip that vibrates atan ultrasonic frequency. The vibrating tip of the handpiece is utilizedto disintegrate or “emulsify” the cataractous lens. This processnecessarily generates lens fragments or particles within the eye thatcan cause irreparable physical damage to corneal endothelial cells ifthose cells are left unprotected. The corneal endothelial cells arenormally protected during the phacoemulsification procedure by injectinga viscoelastic material (e.g., hyaluronic acid) into the eye to form aprotective barrier over the corneal endothelial cells. However, evenwith the presence of the viscoelastic material, lens particles continueto move in the eye, particularly when the viscoelastic material isremoved by a combined irrigating/aspiration handpiece following thephacoemulsification of the lens, prior to insertion of an artificiallens.

Due to continuous irrigation and aspiration, usually there is a lot ofturbulence in the anterior chamber, within which non-aspirated lensfragments move around. In addition, the ultrasonic vibrations producedby the tip of the phacoemulsification handpiece push the lens fragmentsaway from the tip thereby making it difficult to aspirate the fragmentsvia the aspiration line in the tip of the handpiece. The movement ofthese lens fragments can cause damage to the surrounding tissue.

In addition to the lens fragments, damage may result directly from theturbulent flow of fluids intraocularly or from bubbles generated in theintraocular fluids by the phacoemulsification handpiece. Air bubblesgenerated during intraocular surgery have been shown to result in severeinjury to the corneal endothelium in as little as twenty seconds. Theturbulent flow of fluids may also cause tissue fragments to impact thedelicate corneal endothelial cells or other intraocular tissues, therebycausing mechanical trauma to such tissues.

For further background regarding these problems, please refer to thefollowing articles: Kim, et al., “Corneal endothelial damage by airbubbles during phacoemulsification”, Archives of Ophthalmology, volume115, pages 81-88, 1997; Beesley et al., “The effects of prolongedphacoemulsification time on the corneal endothelium”, Annals ofOphthalmology, volume 18, no. 6, pages 216-219, 1986; Kondoh et al.,“Quantitative measurement of the volume of air bubbles formed duringultrasonic vibration”, Folia Ophthalmogica Japan, volume 45, no. 7,pages 718-720, 1994 and Kim et al., Investigative Ophthalmology & VisualScience, volume 37, no. 3, S84, 1996.

The fluid dynamics of intraocular irrigating solutions is also importantduring vitrectomy procedures and various other types of intraocularsurgical procedures. Turbulence in intraocular fluids may also resultfrom the movements of reciprocating vitrectomy handpieces, thealternating vacuum and irrigation modes of irrigation/aspirationhandpieces and movements of other surgical handpieces and devicesutilized in such procedures. The elimination or reduction of suchturbulence helps to protect the retina and other tissues located in theposterior segment of the eye, as well as tissues located in the anteriorsegment of the eye, such as the corneal endothelial cells.

In view of these potential complications, there is a need forintraocular irrigating solutions having improved physical propertiesthat: (1) reduce the potential for turbulence within the anterior andposterior chambers of the eye, (2) help to contain the movement oftissue fragments and air bubbles within the eye, and (3) facilitate theremoval of lens fragments and other tissue fragments by making it easierfor the surgeon to track the fragments with the tip of the surgicalhandpiece. The present invention is directed to fulfilling this need.Specifically, the present invention is directed to the provision of anirrigating solution that provides for greater control of the movement oftissue fragments, air bubbles and other particles duringphacoemulsification, vitrectomy and other intraocular surgicalprocedures. This control of particle movement is fundamentally differentfrom the above-discussed use of a layer of viscoelastic material toprotect the corneal endothelial cells by means of a cushioning effect.The irrigating solution of the present invention is designed to providea protective effect beyond that obtained by means of viscoelasticagents.

SUMMARY OF THE INVENTION

The present invention is directed to the provision of intraocularirrigating solutions that help to prevent the risk of damage tointraocular tissues, while facilitating the efficiency of the surgicalprocedures. The irrigating solutions of the present invention are lowviscosity solutions that exhibit less turbulence in the presence ofphacoemulsification handpieces and other intraocular surgical devices.These solutions also restrain the movement of air bubbles and tissuefragments within the eye, and generally dampen the impact of ultrasonichandpieces, liquefracture handpieces, irrigation/aspiration handpieces,microscissors, vitrectomy handpieces and other surgical devices onintraocular tissues. The restrained movement of lens fragments withinthe eye protects ophthahmic tissues, and facilitates a more efficientsurgical procedure by enabling the ophthalmic surgeon to locate andremove lens fragments more readily.

The intraocular irrigating solutions of the present invention have aviscosity greater than that of aqueous humor, but preferably have asurface tension similar to that of aqueous humor. Existing irrigatingsolutions generally have a viscosity similar to that of aqueous humor,but have surface tension higher than that of aqueous humor.

The present inventors have found that a slight enhancement of theviscosity of intraocular irrigating solutions greatly improves theability of the solutions to protect intraocular tissues by containingthe movement of tissue fragments and generally reducing the turbulenceof the intraocular fluids, thereby making it easier for the fragments tobe tracked and removed via aspiration. This slight enhancement ofirrigating solution viscosity is also beneficial in vitrectomyprocedures because it reduces the pulsatile movement of the retinaltissue and limits collateral tissue damage in the eye. The reduction ofpulsatile movement of retinal tissue is particularly important in caseswhere the retina is partially detached.

The overall performance of the irrigating solutions of the presentinvention can be further enhanced by including an agent which reducesthe surface tension to a level comparable to that of aqueous humor,thereby making the solutions more physiological.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the effect of viscosity on flow rate; and

FIG. 2 is a graph showing the relationship between HPMC concentrationand accumulation rate.

DETAILED DESCRIPTION OF THE INVENTION

The irrigating solutions of the present invention comprise a balancedelectrolyte solution and an amount of a biologically compatibleviscosity-adjusting agent sufficient to enhance the viscosity of theelectrolyte solution.

The electrolyte solution utilized in the present invention willtypically be a balanced salt solution, such as BSS™ (Balanced SaltSolution) Sterile Irrigating Solution manufactured by AlconLaboratories, Inc., or BSS PLUS™ (Balanced Salt Solution) SterileIrrigating Solution, also manufactured by Alcon Laboratories, Inc.However, the invention is not limited relative to the types of balancedsalt solutions or other electrolyte/nutrient solutions that may beutilized as a building block for the solutions of the present invention.

The agents utilized to adjust the viscosity of the electrolyte solutionwill comprise one or more compounds that are compatible with intraoculartissues, such as: chondroitin sulfate, sodium hyaluronate or otherproteoglycans; cellulose derivatives, such as hydroxypropylmethylcellulose (“HPMC”), carboxy methylcellulose (“CMC”), andhydroxyethyl cellulose (“HEC”); collagen and modified collagens;galactomannans, such as guar gum, locust bean gum and tara gum, as wellas polysaccharides derived from the foregoing natural gums and similarnatural or synthetic gums containing mannose and/or galactose moietiesas the main structural components (e.g., hydroxypropyl guar); xanthangum; gellan gums; alginate; chitosans; polyvinyl alcohol; carboxyvinylpolymers (e.g., carbomers such as the Carbopol™ brand polymers availablefrom B.F. Goodrich); and various other viscous or viscoelastomericsubstances, including but not limited to those described in U.S. Pat.No. 5,409,904 (Hecht, et al.), the entire contents of which are herebyincorporated by reference in the present specification.

The following patent publications may be referred to for further detailsconcerning the above-listed viscosity-enhancing agents: U.S. Pat. No.4,861,760 (gellan gums); U.S. Pat. No. 4,255,415 and WIPO PublicationNo. WO 94/10976 (polyvinyl alcohol); U.S. Pat. No. 4,271,143(carboxyvinyl polymers); WIPO Publication No. WO 99/51273 (xanthan gum);and WIPO Publication No. WO 99/06023 (galactomannans). The entirecontents of the foregoing references pertaining to the structures,chemical properties and physical properties of the respective viscosityenhancing agents described above are hereby incorporated in the presentspecification by reference.

The above-described viscosity-adjusting agents will be utilized in anamount sufficient to provide the irrigating solutions of the presentinvention with an enhanced viscosity. As utilized herein, the phrase“enhanced viscosity” means a viscosity which is greater than theviscosity of aqueous humor and prior irrigating solutions, both of whichgenerally have viscosities of approximately 1 centipoise (“cps”). Theirrigating solutions of the present invention will typically haveviscosities of from greater than 1 cps to about 15 cps, preferably fromabout 2 to about 7 cps.

The amount of viscosity adjusting agent utilized will vary depending onthe degree of viscosity enhancement desired and the specific agent oragents selected. However, the concentration of the viscosity-adjustingagent in the irrigating solutions of the present invention willtypically range from about 0.1 to about 1.0 weight/volume percent (“w/v%”) for polymers such as HPMC.

It should be noted that it is necessary to achieve a balance between:(a) enhancing the viscosity of the solution, and (b) maintaining asolution viscosity that is acceptable for use with theirrigation/aspiration system employed during intraocular surgicalprocedures. FIG. 1 of the accompanying drawings is a graph showing theflow rate of irrigating solutions of different viscosities through anormal irrigation/aspiration tip in the Series 20000 Legacy™ (“STTL”)surgical operating system available from Alcon Laboratories, Inc. Duringgeneration of these data, all the settings on the STTL system weredefault instrumental settings. FIG. 1 clearly shows the effect ofincreasing viscosity on flow rate of the irrigating solution, which isusually flowing under gravity.

During a surgical procedure, aspiration is carried out by applyingvacuum through the tip of a surgical handpiece. Generally, the maximumvacuum or suction capability of the system is such that the irrigationrate is higher than the aspiration rate to maintain positive flow.Hence, the increase in viscosity of the irrigation solution should besuch that the flow rate remains greater than the maximum aspirationrate. FIG. 2 of the accompanying drawings illustrates this point.

Increasing the concentration of the viscosity-adjusting agent increasesthe viscosity of the solution, so at the same bottle height, the normalgravity fed irrigation flow rate of fluid into the eye decreases. As thenet irrigation rate decreases, the effective aspiration rate, which iscontrolled independently by a peristaltic pump on the STTL, increases.Hence, the accumulation rate goes from a positive to a negative value. Aminimum irrigation rate of 1 milliliter/minute of aspiration is neededto prevent drying up of the tissue. These competing factors must bebalanced. In the case of HPMC, it has been determined that a HPMCconcentration of 0.27 w/v % provides the desired level of viscosityenhancement without impeding normal irrigation and aspiration functions.It should be noted that this ideal concentration was determined usingHPMC (E4M) in connection with the STTL surgical operating system and astandard phacoemulsification tip. The ideal concentration may varysomewhat, depending on the surgical operating system andphacoemulsification tip utilized.

The preferred viscosity-adjusting agent is hydroxypropylmethylcellulose(“HPMC”). The present inventors have found that the addition of HPMC toa conventional balanced salt solution results in a significant reductionin turbulence during intraocular surgery, relative to the turbulenceseen with the balanced salt solution alone. The preferred concentrationof HPMC is about 0.2 to 0.3 w/v %, but this range may vary slightlydepending on the particular ophthalmic surgical system being utilizedand the instrument settings of that system. Irrigating solutionscontaining this concentration of HPMC will have a viscosity of about 4to 6 cps. The most preferred viscosity-adjusting agent is HPMC (E4M) ata concentration of 0.22 to 0.27 w/v %.

As indicated above, the irrigating solutions of the present inventionpreferably also include an agent to modify the surface tension of thesolutions so as to resemble the surface tension of the aqueous humor.The surface tension of the aqueous humor is approximately 50 dynes percentimeter (“dynes/cm). The irrigating solutions of the presentinvention will therefore preferably have a surface tension in the rangeof 40 to 60 dynes/cm or somewhat less.

It should be noted here that viscosity can be increased by anappropriate agent without affecting surface tension, and that surfacetension can be reduced to the level of aqueous/vitreous humor byinclusion of an appropriate surface-active agent independent ofviscosity. Thus, these two physical properties of irrigating solutionsare independent of each other. However, in some cases, theviscosity-adjusting agent may also function as the surface tensionreducing agent. This is true with respect to the preferred embodiment ofthe present invention, wherein HPMC is utilized both as aviscosity-adjusting agent and a surface tension reducing agent.

In other cases, it may be necessary to add a separate agent to theirrigating solution for purposes of reducing the surface tension of thesolution. Possible agents which can be utilized for this purposeinclude: Polyoxyl 35 castor oil (Cremophore™ EL and Cremophore™ EL-P,available from BASF Corp.), Polyoxyl 40 Hydrogenated Castor Oil(HCO-40), Solutol™ HS 15 (BASF Corp.), Polysorbate 80, Tocophersolan(TPGS), and other ophthalmically acceptable surface active agents.

The following examples are provided to further illustrate variousfeatures of the present invention.

EXAMPLE 1

Component Amount (w/v %) Function HPMC (E4M) 0.1 to 0.3 Viscosity andSurface Tension Modifier Sodium Chloride 0.744  Tonicity Agent PotassiumChloride 0.0395 Essential Ion Dibasic Sodium Phosphate 0.0433 BufferingAgent (Anhydrous) Sodium Bicarbonate 0.219% + 20% xs PhysiologicalBuffer Hydrochloric Acid Adjust pH pH Adjust Sodium Hydroxide Adjust pHpH Adjust Water for Injection 100% Vehicle

The above-described formulation may be prepared as follows: First, thewater for Injection is brought close to boiling or at boiling. The HPMCis then slowly added to the water under continuous stirring tothoroughly disperse it in the water. Then the mixture is slowly allowedto cool, stirring continuously. Once at room temperature, the mixtureshould start clearing up. Then the mixture is stored overnight in anappropriate container to fully hydrate the HPMC. The following day, theremaining ingredients are added to the HPMC solution, additional waterfor injection is added if needed to bring the solution to final volume,and the final solution is filtered, packaged in bottles and autoclaved.

EXAMPLE 2

Component Amount (w/v %) Function HPMC (E4M) 0.1 to 0.3 Viscosity andSurface Tension Modifier Sodium Chloride 0.64  Tonicity Agent PotassiumChloride 0.075 Essential Ion Calcium Chloride (Dihydrate) 0.048Essential Ion Magnesium Chloride 0.03  Essential Ion (Hexahydrate)Sodium Acetate (Trihydrate) 0.039 Buffering Agent Sodium Citrate(Dihydrate) 0.17  Buffering Agent Hydrochloric Acid Adjust pH pH AdjustSodium Hydroxide Adjust pH pH Adjust Water for Injection 100% Vehicle

The above-described formulation may be prepared by means of the methoddescribed in Example 1, above.

EXAMPLE 3

Three solutions were prepared and tested to evaluate the physicalproperties of the solutions of the present invention versus relatedsolutions. The solutions tested and the respective physical propertiesof the solutions were as follows:

Osmolality Viscosity Surface Tension Solution mOsm/kg (cps) dynes/cm²BSS* 304, 305 1.02, 1.06 70, 73 BSS + 0.05% 305, 305 0.99, 1.01 43, 43cremophor BSS + 0.3% 320, 322 6.9, 7.0 48, 49 HPMC (grade E4M) *Asutilized in the above table, the term “BSS” refers to BSS ™ (BalancedSalt Solution) Sterile Irrigating solution manufactured by AlconLaboratories, Inc., Fort Worth, Texas.

As indicated above, the addition of 0.3% HPMC to the BSS solutionincreased the viscosity from approximately 1 cps to 7 cps, and reducedthe surface tension from approximately 71.5 dynes/cm to approximately48.5 dynes/cm. Thus, the addition of this amount of HPMC increased theviscosity of the balanced salt solution and reduced its surface tension,in accordance with the basic principles of the present invention.Conversely, the addition of 0.05% cremophor to the balanced saltsolution had no effect on viscosity, but reduced the surface tension ofthe balanced salt solution from approximately 71.5 dynes/cm to 43dynes/cm.

The above-identified solutions were tested in a simulated intraocularsurgery model to determine if the addition of cremophor and HPMC to thebalanced salt solution affected the performance of the solution relativeto the turbulence of the solution during intraocular surgicalprocedures. It was determined that the addition of cremophor to thebalanced salt solution, although effective in reducing the surfacetension of the solution, had little if any effect on the performance ofthe balanced salt solution. However, the solution containing HPMCdemonstrated much less turbulence than the balanced salt solution alone.This turbulence was judged based on the movement of air bubbles and themovement of lens fragments.

The spinning and rotation of lens fragments seen with the balanced saltsolution alone was reduced significantly by the inclusion of HPMC in thesolution. The dampening of the movement of the lens particlesfacilitated an easier removal of the particles from the eye during thesimulated surgical procedure. This dampening effect facilitated a moreefficient surgical procedure and reduced the time required for theprocedure.

Conversely, there appeared to be no difference between the balanced saltsolution alone and the balanced salt solution containing cremophor withregard to bubble formulation, rate of flow or the visual hydrodynamicsof the irrigating solutions.

The foregoing results confirm that the addition of a small amount of aviscosity enhancing agent reduces the turbulence of intraocular fluidsduring surgical procedures, dampens the movement of bubbles and lensfragments, and generally renders the procedure more efficient.

1. An ophthalmic pharmaceutical composition for irrigating oculartissues during an intraocular surgical procedure, comprising a balancedsalt solution and an amount of a viscosity-adjusting agent sufficient toprovide the composition with a viscosity of 2 to 7 cps, said compositionhaving a surface tension of 40 to 60 dynes/cm.
 2. A compositionaccording to claim 1, wherein the viscosity-adjusting agent is selectedfrom the group consisting of proteoglycans, cellulose derivatives,collagen or modified collagen, galactomannans, xanthan gums, gellangums, alginate, chitosans, polyvinyl alcohol, and carboxyvinyl polymers.3. A composition according to claim 2, wherein the viscosity-adjustingagent comprises a cellulose derivative.
 4. A composition according toclaim 3, wherein the viscosity-adjusting agent comprises hydroxypropylmethylcellulose.
 5. A composition according to claim 4, wherein theconcentration of hydroxypropyl methylcellulose in the composition is 0.1to 1.0 w/v %.
 6. A composition according to claim 5, wherein theconcentration of hydroxypropyl methylcellulose in the composition is 0.1to 0.3 w/v %.
 7. A composition according to claim 6, wherein theconcentration of hydroxypropyl methylcellulose in the composition is 0.2to 0.3 w/v %.
 8. A composition according to any one of claims 1 to 7,wherein the balanced salt solution is an electrolyte/nutrient solution.9. A method of irrigating intraocular tissues during an ophthalmicsurgical procedure, which comprises bathing the intraocular tissues withan irrigating solution containing an amount of a viscosity-adjustingagent sufficient to provide the solution with a viscosity of 2 to 7 cps,whereby the turbulence of the solution during the surgical procedure isreduced.
 10. A method according to claim 9, wherein theviscosity-adjusting agent is selected from the group consisting ofproteoglycans, cellulose derivatives, collagen or modified collagen,galactomannans, xanthan gums, gellan gums, alginate, chitosans,polyvinyl alcohol, and carboxyvinyl polymers.
 11. A method according toclaim 10, wherein the viscosity-adjusting agent comprises a cellulosederivative.
 12. A method according to claim 11, wherein theviscosity-adjusting agent comprises hydroxypropyl methyl cellulose. 13.A method according to claim 12, wherein the concentration ofhydroxypropyl methylcellulose in the solution is 0.1 to 1.0 w/v %.
 14. Amethod according to claim 13, wherein the concentration of hydroxypropylmethylcellulose in the solution is 0.1 to 0.3 w/v %.
 15. A methodaccording to claim 14, wherein the concentration of hydroxypropylmethylcellulose in the solution is 0.2 to 0.3 w/v %.
 16. A methodaccording to any one of claims 9 to 15, wherein the irrigating solutionhas a surface tension of 40 to 60 dynes/cm.
 17. A method according toany one of claims 9 to 15, wherein the irrigating solution is anelectrolyte/nutrient solution.